Anti-scube1 antibody having high internalization capacity in leukemia

Abstract

The present disclosure relates to anti-SCUBE1 antibodies, antigen-binding fragments thereof, and antibody drug conjugates (ADCs), as well as methods of treating and/or preventing SCUBE1-expressing cancers.

What is claimed is: 
     
         1 . An antibody or antigen-binding fragment thereof that specifically binds to SCUBE1, comprising a heavy chain variable region and/or a light chain variable region, wherein:
 the heavy chain variable region comprises:
 a complementary determining region (CDR) sequence CDRH1 comprising the amino acid sequence of GYTFTSYAMH (SEQ ID NO: 1) or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 1; 
 a CDRH2 sequence comprising the amino acid sequence of YINPYNDVSRYNEKFQG (SEQ ID NO: 2) or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 2; and 
 a CDRH3 sequence comprising the amino acid sequence of EARPTSAPYFDV (SEQ ID NO: 3) or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 3; and wherein: 
   the light chain variable region comprises:
 a CDRL1 sequence comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 4) or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 4; 
 a CDRL2 sequence comprising the amino acid sequence of WTSTRES (SEQ ID NO: 5) or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 5; and 
 a CDRL3 sequence comprising the amino acid sequence of KQSYNLFT (SEQ ID NO: 6) or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6. 
   
     
     
         2 . The antibody or antigen-binding fragment thereof according to  claim 1 , wherein:
 the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7; and/or   the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8.   
     
     
         3 . The antibody or antigen-binding fragment thereof according to  claim 1 , wherein the antibody is a monoclonal antibody, chimeric antibody, humanized antibody, or human antibody. 
     
     
         4 . A vector encoding the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         5 . A genetically engineered cell expressing the antibody or antigen-binding fragment thereof as defined in  claim 1 . 
     
     
         6 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as defined in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         7 . An antibody-drug conjugate (ADC) comprising an anti-SCUBE1 antibody, or the antigen-binding fragment thereof as defined in  claim 1 , conjugated to a cytotoxin. 
     
     
         8 . The ADC of  claim 7 , wherein the ADC has the structure of the following formula:
   Ab-(Z-L-D) n ,   wherein an antibody or antigen-binding fragment thereof (Ab) is conjugated (covalently linked) to a linker (L), through a chemical moiety (Z), and further to a cytotoxin moiety (“drug,” D); and wherein n represents the number of drugs linked to the antibody.   
     
     
         9 . The ADC of  claim 8 , wherein n is from about 1 to about 20. 
     
     
         10 . The ADC of  claim 7 , wherein the cytotoxin is a microtubule-binding agent (for instance, maytansine or a maytansinoid), an amatoxin,  Pseudomonas  exotoxin A, deBouganin, diphtheria toxin, saporin, an auristatin, an anthracycline, a calicheamicin, irinotecan, SN-38, a duocarmycin, a pyrrolobenzodiazepine, a pyrrolobenzodiazepine dimer, an indolinobenzodiazepine, an indolinobenzodiazepine dimer, or a variant thereof. 
     
     
         11 . The ADC of  claim 7 , wherein the cytotoxin is a DNA-intercalating agents, (e.g., anthracyclines), agents capable of disrupting the mitotic spindle apparatus (e.g.,  Vinca  alkaloids, maytansine, maytansinoids, and derivatives thereof), RNA polymerase inhibitors (e.g., an amatoxin, such as .alpha.-amanitin, and derivatives thereof), and agents capable of disrupting protein biosynthesis (e.g., agents that exhibit rRNA N-glycosidase activity, such as saporin and ricin A-chain). 
     
     
         12 . The ADC of  claim 7 , wherein the cytotoxin is MMAE. 
     
     
         13 . A pharmaceutical composition comprising the ADC of  claim 7  and a pharmaceutically acceptable carrier. 
     
     
         14 . A method of treating and/or preventing a SCUBE1-expressing cancer in a subject, said method comprising administering the ADC of  claim 7  to the subject. 
     
     
         15 . The method of  claim 14 , wherein the cancer is a blood cancer. 
     
     
         16 . The method of  claim 14 , wherein the cancer is leukemia. 
     
     
         17 . The method of  claim 14 , wherein the cancer is leukemia caused by MLL rearrangements. 
     
     
         18 . The method of  claim 14 , wherein the cancer is AML. 
     
     
         19 . The method of  claim 14 , wherein the cancer is MLL-r AML. 
     
     
         20 . A genetically engineered cell comprising the vector of  claim 4 .